Hepatitis C virus (HCV) is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 150 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulins treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.
Various clinical studies have been conducted with the goal of identifying pharmaceutical agents capable of effectively treating HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone and in combination with other antiviral agents. Such studies have shown that a substantial number of the participants do not respond to these therapies, and of those that do respond favorably, a large proportion were found to relapse after termination of treatment.
Until recently, interferon (IFN) was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Recently, interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone. However, the side effects caused by IFN are not alleviated with this combination therapy.
Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.
General Viral polymerases are attractive targets for antiviral drug development. For example, inhibitors of Viral RNA polymerase activity have been described; see, for example, JAEN, Juan, et. al., WO 0177091, Altamura et. al., WO 00/06529 and Bailey et. al., WO 00/10573, which references are incorporated by reference herein.
The HCV protein NS5B is an RNA dependent RNA polymerase, see, e.g., Lohmann et al. (1997) J. Virol. 71:8416–8428, Behrens et al. (1996) EMBO J. 15:12–22 and Ishido et al. (1998) Biochem. Biophys. Res. Comm. 244:35–40, which references are incorporated by reference herein. The sequence of various genotypes of HCV NS5B are known (Kato et al. (1990) Proc. Natl. Acad. Sci. USA. 87:9524–9528; Webster, G., et al. (2000) Balliere's Clinical Gastroenterology 14, 229–240; van Doom, L. J. (1994) J. of Medical Virology 43, 345–356; Houghton, M. (1996) Hepatitis C viruses Fields Virology: Third Edition, edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Lippincott-Raven Publishers, Philadelphia, pp. 1035–1058; Lau, J. Y. et. al., J Infect Dis. 1995, 171(2), 281–9). However, NS5B contains sequence motifs that are highly conserved among all the RNA-dependent RNA polymerases characterized to date.